tbuckley/cabot-search huggingface dataset:
Comprehensive genomic analysis of salivary gland carcinomas in a Chinese population.
Authors: Hao Lu, Xi Zhang, Shengwen Liu, Wanlin Xu, Yun Zhu, Yifan Wu, Xingjun Qin, Guoxin Ren, Qing Hao, Liwen Zhang, Lijie Guo, Wenjun Yang
Journal: Journal of Clinical Oncology (2023)

e18094 Background: Salivary gland carcinomas (SGCs) represent a heterogeneous group of poorly characterized head and neck tumors, which are rare and challenging to treat. A strategy based on molecular screening and targeted therapy seems to be the best approach for treating patients with SGCs in the future, whereas the genomic mechanisms of SGCs are largely unclear. Methods: A total of 49 patients with histologically confirmed SGCs, including mucoepidermoid carcinoma (MEC, n = 10), adenoid cystic carcinoma (ACC, n = 20), carcinoma ex pleomorphic adenoma (cxPA, n = 10) and other pathological types (n = 9) were enrolled in our study. Tumor tissue specimens were collected and targeted next-generation sequencing for 450 cancer-related genes was performed in OrigiMed (Shanghai, China), a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: In all samples, the most frequently mutated genes were MYB (26.53%), TP53 (26.53%), ERBB2 (12.24%), KMT2D (12.24%), and TERT (12.24%). Actionable genes included ERBB2 (12.2%), PIK3CA (8.2%), ATM (4.1%), CDKN2A/B (4.1%), and EGFR (4.1%). Among these patients, female patients accounted for a higher proportion in ACC compared to that in MEC and cxPA (ACC: 65%, MEC: 30%, cxPA: 30%). Gene fusions/rearrangements were identified in 13 tumors, and 10 (76.9%) had evidence of MYB-NFIB fusion, which may represent an important new therapeutic target for ACC. Higher frequency of MYB (p &lt; 0.0001) and EP300 (p = 0.0445) mutations was also identified in ACC compared with that in other types. Mutational frequencies of TP53 (p = 0.0096) and ERBB2 (p = 0.0228) were obviously higher in cxPA, whereas the frequency of CCNE1 (p = 0.0433) mutations were significantly higher in MEC compared with those in other types. The gene mutations of Chinese SGCs were mainly enriched in RTK/RAS (56.7%), TP53 (40.8%), Notch (34.5%), and PI3K (30.5%) signaling pathways. Conclusions: This report revealed the molecular characteristics of Chinese SGC patients diagnosed with different pathological types, which would be helpful for the investigation of the underlying genomic mechanisms of SGC. Our result highlights the potential role of gene alterations, many of which could conceivably be actionable with targeted therapies.
Predicting survival and prognosis of postoperative breast cancer brain metastasis: A population-based retrospective analysis.
Authors: Nie Yan, Lu Zinan, Gang Sun
Journal: Journal of Clinical Oncology (2023)

e14011 Background: The study aimed to construct a novel predictive clinical model to evaluate the overall survival (OS) of patients with postoperative brain metastasis of breast cancer (BCBM) and validate its effectiveness. Methods: From 2010 to 2020, a total of 310 female patients with BCBM were diagnosed in The Affiliated Cancer Hospital of Xinjiang Medical University, and were randomly assigned to the training cohort and the validation cohort. Another 173 BCBM patients were collected from the Surveillance, Epidemiology, and End Results Program (SEER) database as an external validation cohort. In the training cohort, the least absolute shrinkage and selection operator (LASSO) Cox regression model was used to determine the fundamental clinical predictive indicators and the nomogram was constructed to predict OS. The model capability was assessed using receiver operating characteristic, C-index, and calibration curves. Kaplan–Meier survival analysis was performed to evaluate clinical effectiveness of the risk stratification system in the model. The accuracy and prediction capability of the model were verified using the validation and SEER cohorts. Results: LASSO Cox regression analysis revealed that lymph node metastasis, molecular subtype, tumor size, chemotherapy, radiotherapy, and lung metastasis were statistically correlated with BCBM. The C-indexes of the survival nomogram in the training, validation, and SEER cohorts were 0.714, 0.710, and 0.670, respectively, which showed good prediction capability. The calibration curves demonstrated that the nomogram had great forecast precision, and a dynamic diagram was drawn to increase the maneuverability of the results. The R showed that the OS of low-risk patients was considerably better than that of high-risk patients ( P &lt;0.001). Conclusions: The nomogram prediction model constructed in this study has a good predictive value, which can effectively evaluate the survival rate of patients with postoperative BCBM.
Tumor treating fields (TTFields) therapy skin safety and prevention strategy using a fractionated schema protocol (3-days on/1-day off), effect on skin adverse events.
Authors: Na Tosha N. Gatson, Sara Ornelas, Jesse Manikowski, Steven A Toms, Erika Leese
Journal: Journal of Clinical Oncology (2023)

e14030 Background: Tumor Treating Fields (TTFields) therapy is a locoregional, noninvasive modality currently approved for newly diagnosed (nd) and recurrent (r) CNS WHO grade 4 astrocytomas and glioblastoma (GBM), as well as pleural mesothelioma. TTFields are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression, and are generated by a portable device, delivered by skin-placed arrays. TTFields therapy is not associated with systemic toxicities, nor significant toxicities to healthy tissues or organs within the body; the most commonly associated adverse event (AE) is mild-to-moderate skin irritation beneath arrays, which can typically be managed with appropriate prophylaxis and timely intervention strategies (Lacouture et al 2014 and 2020). Here we report safety outcomes with a novel 3-day on/1-day off protocol strategy that aims to prevent and minimize skin irritation and limit treatment interruptions. Methods: In this dual center, retrospective analysis, adult patients with grade 4 ndGBM or rGBM followed a 3 days-on (72-80 h) and 1 day-off (16–24 h) TTFields therapy use schedule, with skin specific wound prevention guidance (barrier forming moisturizing topical creams and selenium-based shampoos) during the ‘off day’. Information on the presence and severity of skin AEs was collected from patient charts. Results: Adult patients (N = 76) received TTFields therapy with the 3-on/1-off protocol between 2015 and 2021 at 2 healthcare centers in the United States. Median age was 57 years (range 25–81 years) and mean time on TTFields therapy was 73 weeks. Skin AEs occurred in 5% of patients on the 3-day on/1-day off protocol, as compared to 16% and 52% reported in the randomized, phase 3 EF-11 (NCT00379470) and EF-14 (NCT00916409) studies in patients with rGBM and ndGBM, respectively. As in the clinical studies, most AEs were mild in nature. All patients who had a skin AE, prior to starting the 3-days on/1-day off protocol, received treatment to resolve the AE. In addition, no patients had to discontinue TTFields therapy or modify array placement due to skin AEs while on the 3-on/1-off protocol. Conclusions: These real-world clinical practice data confirm the positive known safety profile of TTFields therapy and are consistent with findings from clinical studies. Mild-to-moderate skin irritation is the AE most commonly associated with TTFields therapy, which is mostly manageable and resoluble. These data suggest that skin irritation could be further reduced with active preventative approaches, as described in the fractionated schema (3-days on/1-day off) protocol.
Incidence of metachronous peritoneal metastases for intrahepatic cholangiocarcinoma after curative resection: A single center cohort analysis.
Authors: Safak Gül-Klein, Wenzel Schöning, Georg Lurje, Eriselda Keshi, Matylda Zofia Kuzinska, Raschzok Nathanael, Felix Krenzien, Miguel Enrique Alberto Vilchez, Wolf Ramackers, Peter C. Thuss-Patience, Johann Pratschke, Beate Rau, Uwe Pelzer
Journal: Journal of Clinical Oncology (2023)

e16199 Background: The impact of metachronous peritoneal metastases (m-pm) on survival after curative resection for intrahepatic cholangiocarcinoma (iCCA) is poorly understood, while there is some knowledge to the occurrence of pulmonary and hepatic metastases. Studies are needed to analyze the impact of advanced metastatic disease for m-pm for iCCA after curative resection. Methods: At the Charité - Universitätsmedizin Berlin, a total of 1979 patients with the general diagnosis of cholangiocellular carcinoma were discussed in interdisciplinary tumor conferences from 2010 to 2022. Results: At the Charité - Universitätsmedizin Berlin, a total of 1979 patients with the general diagnosis of cholangiocellular carcinoma were discussed in interdisciplinary tumor conferences from 2010 to 2022. iCCA was present in 269 cases and proven histopathological results were documented at our hospital in 227 patients. Out of these, 209 patients underwent curative resection, while no advanced tumor disease leading to termination of the indicated operation were found. Two patients presented limited synchronous peritoneal metastases (s-pm) intraoperatively. The postoperative histopathological result presented N0-status in 113 patients and N+-status in 96 patients. Metachronous metastases were diagnosed in 17 patients after 103 months on average with a mean overall survival (OS) of 108 months. Regarding postoperative complications &gt;3b Clavien-Dindo after the initial surgery one patient died in the early postoperative follow-up within the first 30 days. Complete radical resection (R0) was achieved in 133 patients, while R1-status was recorded in 28 patients. Furthermore seven m-pm patients additionally presented hepatic metastases, five m-pm patients pulmonary metastases, while one m-pm patient showed simultaneous hepatic and pulmonal metastases and one other m-pm patient developed even hepatic, pulmonal and osseous metastases. Neoadjuvant oncologic therapy was performed in two patients, adjuvant therapy was applied in six patients prior to the diagnosis of m-pm. Again, a total of five patients received palliative therapy after diagnosis of m-pm. Nevertheless, one patient underwent pulmonary metastectomy. Conclusions: The primary aim regarding the two s-pm patients was immediate postoperative surgical outcome without complications (&gt;3a according to Clavien-Dindo) and was feasible, regarding the prognostic impact of s-pm for surgical resectability; curative resection seems to be an option. The primary aim for m-pm was OS, while promising outcomes were shown in this study.
The safety and efficacy of cadonilimab in the treatment of advanced and metastatic cervical cancer: A retrospective, real-world study.
Authors: Shi Fan, Tao Wang, Qiying Zhang, Juan Wang, Jin Su, Jing Zhang, Fei Wang, Zi Liu
Journal: Journal of Clinical Oncology (2023)

e17515 Background: Recurrent/metastatic cervical cancer (r/m CC) patients have limited treatment options. Cadonilimab, a PD-1/CTLA-4 bi-specific antibody, was approved in China on 29 June 2022 for the treatment of patients with r/m CC who have progressed on or after platinum-based chemotherapy. As monotherapy provides encouraging safety and efficacy, it may be better combined with another therapy including chemotherapy, radiotherapy, targeted therapy, or immunotherapy. The objective of this retrospective study was to evaluate the safety and efficacy of Cadonilimab monotherapy/combination therapy in patients with advanced r/m CC. Methods: Patients with FIGO stage IIIc2r-IVb CC treated with Cadonilimab containing therapy were enrolled. All patients received at least one dose of Cadonilimab (10mg/kg, Q3W), among them, 5 patients received Cadonilimab monotherapy, 11 patients received concurrent radiotherapy, 19 patients received concurrent chemotherapy, 12 patients received targeted therapy, and 4 patients received local injection s of oncolytic virus. Treatment-related toxicity (TRAEs), objective response rate (ORR) and disease control rate (DCR) were evaluated. Results: 26 patients with a median age of 54 years (40-73 years) were evaluated up to 20 January 2023. As shown in the table, 21 patients were still on treatment, 5 patients were discontinued due to death. In the efficacy-evaluable population(n=24), the ORR was 70.8% (17/24,95% CI:51.2%-90.4%) with 3 (12.5%) CR,14 PR, 2 SD, and the DCR was 79.2%(19/24,95% CI:61.6%-96.7%). Immune-related AEs (irAEs) were all G1-2, and occurred in 4 (16.7%) patients. Main irAEs included hypothyroidism (n=3, 12.5%), fatigue (n=1, 4.2%), loss of appetite (n=1, 4.2%), hematologic toxicity (thrombocytopenia) (n=1, 4.2%), mucositis (n=1, 4.2%), and rash (n=1, 4.2%). Rashes and loss of appetite typically developed after the first cycle of Cadonilimab treatment, while hypothyroidism usually developed after the second or third cycle. 2 (8.3%) patients experienced G3-5 TRAEs, which were thought to be primarily related to chemotherapy. All the 5 deaths were heavily pretreated (≥3 lines) patients who received Cadonilimab monotherapy. Among the 24 patients, only 1 patient delayed treatment after the 1st cycle due to economic reasons. There were no toxic deaths reported. Conclusions: In the real world, Cadonilimab showed a manageable safety profile. Patients with advanced r/m CC tend to benefit from first-line/second-line Cadonilimab containing combination therapies due to the excellent response rates. [Table: see text]
Utility of circulating tumor DNA (ctDNA) as a predictive biomarker for disease monitoring in patients (pts) with cholangiocarcinoma (CCA) before and during adjuvant chemotherapy (ACT): Sub-analysis of the randomized phase 2 STAMP trial.
Authors: Changhoon Yoo, George Laliotis, Hyehyun Jeong, Jae Ho Jeong, Kyu-Pyo Kim, Seonmin Lee, Baek-Yeol Ryoo, Shruti Sharma, Punashi Dutta, Meenakshi Malhotra, Adham A Jurdi, Minetta Liu
Journal: Journal of Clinical Oncology (2023)

4123 Background: Detection of circulating tumor DNA (ctDNA) in blood is a powerful predictive biomarker for identifying molecular residual disease (MRD) post-surgery. Not much is known about the utility of identifying MRD using ctDNA in pts with resected CCA, despite its associated poor prognosis. The STAMP trial (NCT03079427), a randomized phase 2 study comparing adjuvant capecitabine (CAP) to gemcitabine plus cisplatin (GemCis) showed no difference in recurrence-free survival (RFS) and overall survival (OS) between the 2 arms. The goal of this analysis was to evaluate the feasibility of monitoring ctDNA to predict the risk of recurrence in pts with resected CCA. Methods: A total of 254 plasma samples were collected from a cohort of 89 CCA (hilar, N = 43; distal, N = 46) pts post-surgery at 3 separate time points; pre-ACT (baseline, N = 89), on-ACT C5D1 (after 5 cycles of treatment) (N = 88), and on-ACT C8D1 (after 8 cycles of treatment) (N = 77). Longitudinal ctDNA testing was performed using a personalized, tumor-informed ctDNA assay (Signatera, bespoke mPCR-NGS assay). ctDNA results were analyzed and evaluated for its correlation with RFS and OS. Results: At the MRD timepoint (baseline, pre-ACT), 24.7% (22/89) pts were ctDNA-positive, 90.9% (20/22) of whom recurred demonstrating a trend for shorter RFS (HR = 1.7, 95%Cl 0.98-2.8, p = 0.069) compared to ctDNA-negative pts. All pts who remained ctDNA-positive on-ACT at C5D1 (N = 17) and C8D1 (N = 15), recurred clinically with a significantly shorter RFS (HR = 8.1, 95%Cl 4.3-15, p &lt; 0.0001 and HR = 5.0, 95%Cl 2.7-9.4, p &lt; 0.0001, respectively). The primary cancer site (hilar vs distal) or type of ACT (CAP vs GemCis) had no impact on RFS irrespective of ct-DNA result. Pts who remained ctDNA-negative on ACT (N = 56) showed significantly better RFS compared to pts who remained positive (N = 10, HR = 6.6, 95%Cl 3.1-14, p &lt; 0.001), or who turned positive (N = 11, HR = 5.2, 95%Cl 2.54-10.5, p &lt; 0.001). In multivariate analysis including primary tumor site, sex, pathological grade and ACT regimen, positive ctDNA status at baseline (pre-ACT) remained significant for poor RFS (HR = 1.82, 95%CI 1.04-3.18, p = 0.035). Conclusions: Personalized monitoring of ctDNA both pre and on-ACT is feasible and predictive for recurrence in pts with resected CCA. To our best knowledge, this is one of the first reports presenting the clinical implication of ctDNA monitoring on ACT, in pts with CCA. Our findings suggest ctDNA monitoring may help optimize clinical decision-making in pts with resected CCA. Larger prospective studies would be needed to validate the findings of this study. Clinical trial information: NCT03079427 .
Hyperinsulinemia and risk of lethal prostate cancer.
Authors: Veeraya Kate Tanawattanacharoen, Lorelei A Mucci, Edward L. Giovannucci
Journal: Journal of Clinical Oncology (2023)

e17008 Background: Epidemiologic studies have found that insulin-like growth factor (IGF)-1 causally increases prostate cancer incidence and mortality, but the effect of insulin is less clear. IGF-1 and insulin act as mitogens by binding non-selectively to their receptors. To this end, this study tests the hypothesis that high circulating insulin increases risk for lethal (fatal or metastatic) prostate cancer among men with non-metastatic prostate cancer. Methods: The study population was drawn from two U.S.-based longitudinal cohorts: the Health Professionals Follow-Up Study (HPFS) of 51,529 health professionals and the Physicians’ Health Study (PHS) of 29,067 physicians. Pre-diagnostic plasma concentration of C-peptide was used as a proxy for insulin and measured on blood collected in 1993-1995 (HPFS) or 1982 (PHS) and stratified into quartiles for analysis. The empiric lifestyle index (based on body mass index (BMI), physical activity, and diet) for hyperinsulinemia (ELIH) was calculated from questionnaire data. Covariates of interest (age and fasting status at blood draw, BMI, height, clinical stage, and tumor grade) were attained from questionnaires and medical records. We followed patients for development of metastasis or death (lethal) through 2019 (HPFS) and 2015 (PHS). SAS 9.4 and R Studio were used for analyses. Chi-squared tests and Mann Whitney U tests were used to compare differences between groups, and Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% CI. Results: The sample included 2,812 men with 353 lethal prostate cancer events and a mean follow-up of 164 months from diagnosis to death. The mean time from blood draw to cancer diagnosis was 8.1 years. Compared to men with non-lethal prostate cancer, those with lethal disease had significantly more severe clinical grade and stage at diagnosis, higher BMI (25.1 vs 24.6), older age at blood draw (64.5 vs 61.9 years), and higher ELIH index. There were no differences by other covariates. There was no association between pre-diagnostic c-peptide levels and cancer-specific survival in a multivariable model that included clinical stage and grade (HR, 95% CI for high vs. low quartiles: 1.17, 0.83, 1.67). High ELIH was positively associated with risk of lethal prostate cancer (HR, 95% CI: 2.41, 1.36, 4.28), even when controlling for C-peptide (HR, 95% CI: 2.18, 1.20, 3.96). Conclusions: C-peptide levels measured prior to cancer diagnosis were not associated with increased mortality from prostate cancer. Higher ELIH was associated with increased risk of lethal prostate cancer among those diagnosed with prostate cancer, which could be partly mediated by hyperinsulinemia, but other dietary, physical activity, or BMI mechanisms could contribute.
Upper tract urothelial cancer (UTUC): Role of sequencing, molecular subtyping and treatment outcomes.
Authors: Sarah Belay, Wenping Li, Jeanny B. Aragon-Ching
Journal: Journal of Clinical Oncology (2023)

e16578 Background: Upper tract urothelial cancers (UTUCs) are rare forms of urothelial cancer that behave in a more aggressive manner. Treatment response to immunotherapy may be less impactful in the adjuvant setting. Studies suggest molecular subtyping might predict survival outcomes. We seek to determine whether genomic sequencing, molecular subtype signatures can be used to predict patient response to chemotherapy in upper tract urothelial cancers. Methods: UTUC patients seen consecutively at a single institution during a 4-year period were evaluated with IRB approval. Analyses of NGS (next-generation sequencing) using Foundation Medicine or TEMPUS platforms were compiled. Decipher Bladder assay (research use only for UTUC) using a transcriptome microarray to characterize tumor specimens as luminal vs. non-luminal and 4 non-luminal subtypes. Retrospective and descriptive analyses were used to identify predictors of response and survival and therapeutic options patients (pts) underwent. Additional phenotypic factors such as initial staging, tumor location, response to neoadjuvant chemotherapy (NAC), and responses to treatment for localized or metastatic disease were determined. Results: UTUC patients whose clinical and demographic features were available for 23 patients (Male = 7; Female = 16); locally advanced = 9; metastatic = 14. Tumor samples were obtained with Decipher bladder assay (n=4); next-generation sequencing assay (n = 9). Neoadjuvant chemotherapy (NAC) was given in all pts with localized disease and for metastatic disease (n=11 pts). Platinum-based chemotherapy (PBC) resulted in median overall survival (mOS) of 36.6 mos compared to no chemotherapy 22.8 mos at the time of data cut-off. Decipher bladder assay showed basal subtype and mixed basal/claudin-low in 4 patients of whom one achieved stable disease though residual ypT3 after NAC and the 3 achieved progressive disease as best response, all with metastatic disease. NGS showed LOH - 21.01% and ATM truncation in 2 patients with prolonged responses to avelumab maintenance immunotherapy and 2 patients with CDK2A/2B loss with prolonged survival (mOS = 16.8 mos). Additionally, 5 patients were identified as having a TERT promoter variant, though this does not appear to have a significant relationship with survival or disease progression when compared to those without the variant. Conclusions: Results do not identify a specific NGS signature or subtype signature that predicts response to chemotherapy in the neoadjuvant or metastatic setting though receipt of chemotherapy appears to clinically affect outcomes in this small sample of UTUC patients. Further studies are needed to identify specific molecular signatures that would predict responses to therapy.